PROJECT SUMMARY The circulation and clearance of cerebrospinal fluid (CSF) and interstitial fluid (ISF) is imperative for maintaining the brain's homeostatic environment and metabolic needs. Although CSF turnover decreases during normal aging, a decrease in proper CSF and ISF circulation could play a causal role in neurodegenerative disorders, and has been implicated in Alzheimer's disease. While the primary mechanism for CSF clearance described in the literature is through the arachnoid villi, an increasing body of evidence points to the olfactory sensory neuron (OSN) axon bundles through the foramina (holes) of the cribriform plate, the part of the ethmoid bone that separates the cranial cavity from the nasal cavity, as a major route for CSF clearance. However, the cellular basis of this drainage is poorly understood. Intriguingly, decreases in olfactory sensitivity are correlated with aging and neurodegenerative disorders, suggesting damage to this route might be linked to lowered CSF turnover rate. To test this hypothesis, I propose to determine the anatomical substrate of CSF and ISF clearance and the physiological effects of disrupting CSF and ISF clearance through the cribriform plate. To do this I will employ anatomical (histology, microCT imaging) and physiological (CSF flow measurements, gene expression assays, and intracranial pressure (ICP)) techniques. The end results of these studies will be a better understanding of the normal routes of clearance of CSF and ISF, which hopefully can be used to better inform treatments for neurological diseases.